Calcium channel inactivation: Possible role in signal transduction and Ca2+ signaling

Voltage gated Ca2+ channels are major routes for the entry of intracellular Ca2+ coupled to membrane depolarization that appear to vary greatly with respect to their voltage dependence and kinetics. Such variability maybe in part related to the attached signaling properties of the channel, in addition to the transport of calcium. In the present review we consider the possible role of calcium-dependent inactivation of Cav1.2 in Ca2+ signal transduction and signaling of calcium release from the cardiac sarcoplasmic reticulum. We explore the specific roles of Ca2+-sensing calmodulin-binding domains of the C-terminal tail (LA and K) of the channel in mediating Ca2+-induced Ca2+ release and signal transduction. Our experiments point to an intriguing possibility that the C-terminal tail of Cav1.2 may translocate the Ca2+ signal as a part of inactivation mechanism and the corresponding voltage-gated rearrangement of the C-terminus. We show how a dynamic and transient regulation, in a Ca2+-dependent manner, defines molecular events including Ca2+ release and signaling of cAMP-responsive element-binding protein (CREB)-dependent transcription. We propose that such Ca2+-dependent C-tail translocation that also initiates the channel inactivation, may have evolved specifically for the Cav1.2 channel.